Malignant mesothelioma (MM) is frequent in individuals continuously exposed to carcinogenic mineral fibers such as asbestos and erionite, but it is very rare in those with limited or no exposure. Genetics influences susceptibility to MM, and we have recently demonstrated that carriers of germline BAP1 mutations have increased incidence of multiple cancer types, including MM. In some BAP1-mutation carrying families, MM accounts for more than 50% of deaths, and our central hypothesis is that this may be due to increased susceptibility to MM from exposure to modest amounts of asbestos that would normally not cause MM in the general population. The mechanism(s) by which mutated BAP1 causes MM pathogenesis is unknown. Our preliminary data show a previously uncharacterized BAP1 function in the cytoplasm, wherein BAP1 appears to regulate Ca2+ release from the endoplasmic reticulum and, in turn, apoptosis. Our preliminary data also show that monoallelic BAP1 loss increased susceptibility to low doses of asbestos, and that germline BAP1 mutation carriers have higher levels of serum HMGB1, a critical factor for MM development and progression. In addition, our preliminary investigations show that germline BAP1 mutation carriers with MM have significantly prolonged median survival (5 years) compared to sporadic MM (1 year). Therefore, we hypothesize that, on one hand, BAP1 mutation favors malignant transformation by inhibiting apoptosis and therefore increasing the percentage of cells that accumulate genetic damage, and that, on the other hand, BAP1 mutation may impair the aggressiveness of MM cells by either directly altering tumor cell growth or by affecting the tumor microenvironment. We further hypothesize that monitoring blood levels of HMGB1 in family members who carry BAP1 mutations may facilitate early detection of MM. To address the hypotheses, we will examine the following specific aims: (Aim 1) To elucidate the novel cytoplasmic functions of BAP1 and determine whether BAP1 mutations increase resistance to apoptosis by modulating Ca2+ homeostasis. (Aim 2) To determine whether BAP1 mutations increase susceptibility to MM upon exposure to low amounts of asbestos and elucidate why MM may be less aggressive in BAP1 mutation carriers. (Aim 3) To determine whether HMGB1 is increased in individuals with germline BAP1 mutations. To elucidate the role of cytoplasmic BAP1 and its possible contribution to malignancy, we have assembled a unique cohort of families carrying germline BAP1 mutations and have access to unique models. We will elucidate the mechanisms and genetic alterations that lead to MM in BAP1 mutation carriers using a heterozygous BAP1 mouse model and derived cell cultures. Finally, we will evaluate whether HMGB1 can be used as a biomarker so as to improve our ability to monitor these high-risk individuals for early detection of MM, which will directly impact patients because detection of MM at the early stages of MM progression is strongly correlated to increased survival. These studies will also be relevant to the multiple malignancies associated with the BAP1 cancer syndrome.